Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease with high morbidity and mortality, whose etiology and pathogenesis are unknown. The SLE susceptibility at 16q13 was identified previously by at least four independent groups. Recently, we confirmed this linkage in two independent data sets. We found significant evidence of linkage (HLOD = 4.85, alpha = 35%) using a data set consisting of 120 SLE families (82 European-American and 38 African-American), and earlier we reported a suggestive evidence (LOD = 2.01) of linkage based on 37 Hispanic families. Therefore, independent published reports, together with our presented significant evidence, provide overwhelming support for a SLE susceptibility gene at 16q13. Currently, conservative estimates suggest that the susceptibility region spans approximately 20 cM. This grant proposal will apply a unique interdisciplinary approach that will take advantage of genetic epidemiological approaches and microarray techniques to identify the SLE susceptibility gene(s) located at 16q 13. To achieve this goal, Specific Aim 1 is to perform genetic fine mapping at the susceptibility region with microsatellite markers to form approximately an 1 cM map, using all the existing 157 families (37 +120) and analyze these data using genetic linkage methods. We expect to reduce the current candidate susceptibility region to a region of approximately 8-10 cM. Specific Aim 2 is to further narrow the candidate region containing the putative susceptibility gene by genotyping the single nucleotide polymorphism (SNP) markers in the region established in Aim 1 to form a 0.1 cM map or better and to analyze these by linkage disequilibrium (LD) methods. To improve the power of the association study, we will augment our existing 157 pedigrees with data from an additionally available 300 trios. Through this specific aim we expect to reduce the candidate region to about 1-3 cM. Specific Aim 3 is to search potential candidate genes lidentified from the reduced region, using a two-prong approach-- (a) by comparing the differential gene lexpression profiles between a pool of 20 SLE patients and a pool of 20 age, sex, ethnicity matched unrelated, unaffected normal controls, and (b) by identifying the genes from public sequence databases in which priority will be given to biological significance with autoimmune diseases. Specific Aim 4 is to evaluate the selected candidate genes by genotyping a set of 4-6 haplotype 'tagged' SNPs from each of the candidate genes and analyze these by family-based LD methods. The study design and the multidisciplinary expertise of our team strengthen the likelihood of success for this project.